Administration Of Phenobarbitone Research Articles

The effect of long-term administration of phenobarbitone in CF-1 mice

Summary Long-term administration of phenoarbitone to CF-1 mice resulted in a significantly increased incidence and earlier appearance of liver tumours in both male and female animals over those observed in controls. No appreciable differences could be seen in the incidences of other tumours among the treated and control groups.

A PHARMACOKINETIC INTERACTION IN MAN BETWEEN PHENOBARBITONE AND FENOPROFEN, A NEW ANTI‐INFLAMMATORY AGENT

1 The effect of repeated administration of phenobarbitone on the plasma disposition of fenoprofen (±-2-(3-phenoxyphenyl) propionic acid) was investigated in rats and man. 2 The plasma elimination rate constants increased significantly and the rats excreted proportionately more metabolized fenoprofen in the urine. These findings are consistent with an increase in the rate of metabolism of fenoprofen. 3 This interaction between phenobarbitone (and presumably other inducers of drug metabolizing enzymes) and fenoprofen should be considered when evaluating the clinical usefulness of fenoprofen.

Phospholipid synthesis in rat liver endoplasmic reticulum after the administration of phenobarbitone and 20-methylcholanthrene.

1. Phenobarbitone injection did not affect the concentration of phospholipids in the liver endoplasmic reticulum, but it increased the rate of incorporation of [(32)P]orthophosphate into the phospholipids. 20-Methylcholanthrene caused a transient increase in total phospholipid but a decrease in the turnover rate of the phospholipids. 2. Incorporation of [(32)P]orthophosphate into phosphatidylcholine, compared with that into phosphatidylethanolamine, was increased by phenobarbitone injection but decreased by 20-methylcholanthrene injection. 3. The activity of S-adenosylmethionine-phosphatidylethanolamine methyltransferase increased 12h after phenobarbitone injection, when incorporation of [(32)P]orthophosphate into phosphatidylcholine was a maximum, but at other times, and after 20-methylcholanthrene injection, the activity of the enzyme did not correlate with the rate of phosphatidylcholine synthesis. 4. [(14)C]Glycerol was incorporated more rapidly into phosphatidylcholine than into phosphatidylethanolamine, whereas [(32)P]orthophosphate and [(14)C]ethanolamine were incorporated more rapidly into phosphatidylethanolamine than into phosphatidylcholine. 5. Incorporation of [(32)P]orthophosphate into phosphatidylethanolamine of liver slices incubated in vitro was much more rapid than into phosphatidylcholine, and incorporation into phosphatidylcholine was markedly stimulated by addition of methionine to the medium. Changes in the incorporation of [(32)P]orthophosphate into phospholipids observed in vivo after injection of phenobarbitone or methylcholanthrene could not be reproduced in slices incubated in vitro. 6. It is concluded that phenobarbitone injection causes an increased rate of turnover of total phospholipids in the endoplasmic reticulum and an increased conversion of phosphatidylethanolamine into phosphatidylcholine, whereas 20-methylcholanthrene injection depresses both the turnover rate of total phospholipids and the formation of phosphatidylcholine.

Increased Glucuronidation of Bilirubin in Man and Rat by Administration of Antipyrine (Phenazone)

1. Antipyrine in a dose of 3·2 mmol (600 mg) daily for 6 weeks produced a significant fall in both total and unconjugated serum bilirubin concentrations in six patients with Gilbert's syndrome. The maximum reduction in serum bilirubin concentration was seen after 2 weeks of treatment. 2. In the rat, administration of antipyrine in doses of 0·42 and 1·27 mmol 24 h−1 kg−1 (80 and 240 mg 24 h−1 kg−1) for 84 h caused a significant increase in the apparent maximal velocity (Vmax.) for the glucuronidation of bilirubin by liver microsomal preparations when the concentration of either uridine diphosphate glucuronic acid (UDPGA) or bilirubin was altered. There was no significant difference between the apparent Vmax. values attained with the two doses of antipyrine in either set of experiments. Neither the microsomal protein content nor the apparent affinity constant (Km) was altered in these studies. 3. In contrast, administration of phenobarbitone in doses of 0·34 mmol 24 h−1 kg−1 (80 mg 24 h−1 kg−1) caused a significant increase in the microsomal protein content but there was no significant change in the values for the apparent Vmax. or apparent Km for the glucuronidation of bilirubin with various concentrations of both UDPGA and bilirubin.

The effects of chronic phenobarbitone administration and subsequent withdrawal on the activity of rat liver tryptohan pyrrolase and their resemblance to those of ethanol.

Chronic phenobarbitone administration inhibits the apo-(tryptophan pyrrolase) activity in homogenates of rat liver and subsequent withdrawal enhances the enzyme activity by 2.5-fold. Similar effects have been previously produced by chronic ethanol administration and withdrawal, but, whereas NADH may cause the ethanol inhibition, that by phenobarbitone may be mediated by NADPH.

Effect of certain drugs and environmental agents on microsomal enzyme systems

Hepatic microsomal drug metabolizing enzymes induced in rats by p, p′-DDT reach peak activity 5 days after injection, and return to control values on the 15–19th day. Reinduction with different characteristics occurred and persisted for 50 days. Massive doses are used to produce induction in experimental animals. When smaller amounts similar to those given to man therapeutically were used, it was difficult to assess if hepatic induction occurred. There was some evidence of induction after giving diphenylhydantoin, acetylsalicylic acid, and the environmental agent pyrene. Some inhibitory effects were observed after giving phenacetin and trifluoperazine. Administration of DDT and phenobarbitone per os (p.o.) increased nitroanisole demethylase activity in the small intestine. Hepatic microsomal induction produced by phenobarbitone and DDT was independent of the route of administration, and concurrent dosage did not affect the degree of induction. The effect of induction, in relation to combined exposure to pesticides, drugs and other agents, is discussed with regard to DDT storage levels in patients on anticonvulsant therapy.

Urinary excretion of chlorothiazide in rats before and after phenobarbitone administration.

In 8 Ratten wurde vor und nach Phenobarbiton-Behandlung die Urinausscheidung von markiertem Chlorothiazid als mass des Nierenplasma-durchstromes gemessen. Es zeigte sich eine Verdoppelung der Clorothiazid-Ausscheidung in den ersten 12 Stunden nach Phenobarbital-Behandlung. Dieser Effekt ist nicht auf eine Erhöhung microsomaler Enzyme oder Carrier-proteine zurückzuführen, sondern möglicherweise auf eine Erhöhung der Durchblutung.

Studies on the control of glucuronide synthesis in the rat small intestine.

Gastrointestinal surgery was used in order to determine the role of normal food components, bile and pancreatic secretion in the control of mucosal glucuronide synthesis. Furthermore a few rats were treated either intragastrically or intraperitoneally with phenobarbitone. Both the rate of o‐aminophenyl glucuronide synthesis in slices and the activity of UDP glucuronyltransferase in mucosal extracts were studied. In partial jejunectomies no changes were found in glucuronide synthesis when compared with the controls, but in jejunal Thiry‐Vella loops and in duodenal and jejunal blind sacs the glucuronide synthesis rate was significantly lower. In gastro‐jejunostomized rats a transient increase in the glucuronide synthesis rate was noted in the gastro‐jejunostomy area. Phenobarbitone administration did not increase the small intestinal UDP glucuronyltransferase activity when administered either intraperitoneally or intragastrically. The results indicate that the chyme factors are of importance in the control of glucuronide synthesis in the small intestine of the rat, but that phenobarbitone has no effect.

Hepatic amidopyrine N-demethylase activity in the calf

The daily oral administration to calves of phenobarbitone (20 mg./kg.) produces an increase in the activity of amidopyrine N-demethylase in the liver. The induced activity reaches a peak at about 14 days and then falls slowly in spite of the continued administration of phenobarbitone. A single dose of alpha-cyanato-napthalene (ANIT) reduced enzyme activity within 48 hours as also did a single dose of carbon tetrachloride. The effect of a single dose of halothane on hepatic enzyme activity was much less. Pretreatment with phenobarbitone had no influence on the hepatotoxic effect of ANIT whereas pretreatment considerably increased the toxic effects of carbon tetrachloride and of halothane.

A comparison of mouse and rat liver enzymes and their response to treatment with various compounds

The responses of various mouse and rat liver parameters to administration of several pharmacologically-active agents are compared. Similar, but not identical, changes occured in the livers of both species after the administration of chlorpromazine, clofibrate, carbon-tetrachloride and DDT. Greater differences in the responses were observed after administration of phenobarbitone or griseofulvin.

Enhancement of Methyldopa Metabolism with Barbiturate

The spurious increase in serum catecholamine levels associated with methyldopa treatment can be reduced by the simultaneous administration of phenobarbitone. This accelerating effect of phenobarbitone on methyldopa metabolism has been demonstrated in relation to both adrenaline and noradrenaline, and investigations suggest that it is due to the effect of barbiturate on the activity of metabolizing enzymes.

Effects of Cimetidine and Phenobarbitone on Paracetamol Induced Hepatotoxic Rats

The effects of cimetidine and phenobarbitone on paracetamol induced hepatotoxicity were studied in Long Evans Norwegian strain rats of either sexes. Orally administration of paracetamol 150 mg/ kg body weight for 21 days. On 22nd days after treatment there was significant increase of serum Alanine transaminase (AST), Aspartate transaminase (AST) and Alkaline phosphatase (Alk. phos) level. Orally administration of phenobarbitone 20 mg/kg b.w. along with paracetamol produced highly significant rise of serum ALT, AST and Alk. phos, levels as compared to the paracetamol treated group. But simultaneous administration of paracetamol and cimetidine produced significant decrease of serum ALT, AST and Alk. phos.level. When phenobarbitone is used concurrently with paracetamol, induced hepatic microsomal enzyme system which in turn aggravates the paracetamol induced hepatotoxicity but when cimetidine was administered simultaneously with paracetamol inhibited hepatic microsomal enzyme system and exhibits a protective role on paracetamol induced hepatotoxicity.The experiment was designed to demonstrate the effect of paracetamol on hepatotoxicity and its prevention by simultaneous administration of cimetidine. Further experiment was also designed to demonstrate the induction of hepatic microsomal enzyme system (HMES) by phenobarbitone on paracetamol induced hepatotoxicity. DOI: 10.3329/bjpp.v23i1.5725Bangladesh J Physiol Pharmacol 2007; 23(1&2) : 13-15

Repeated derepression cycles of the glucuronolactone dehydrogenase and cytochrome P-450 in the rat liver induced by phenobarbitone administration

Treatment of adult male rats with five doses of phenobarbitone was repeated at 4-day and monthly intervals in order to study the memory of the derepression cycles of glucuronolactone dehydrogenase and cytochrome P-450 in the liver. When the interval was 1 month, further drug treatments resulted in a similar increase of these enzyme levels and the relative liver weight, both during the second and third treatments. If the next treatment was commenced after an interval of 4 days, when the enzyme levels were still high, significantly lower cytochrome P-450 levels were observed after the third, than after the first and second treatments, and furthermore, after the third treatment the decline of cytochrome P-450 was more rapid than after the first phenobarbitone treatment. The increase and decrease of glucuronolactone dehydrogenase activity took place at a considerably slower rate than that of cytochrome P-450. After five phenobarbitone administrations there was a significant increase of cytochrome P-450 and also of glucuronolactone dehydrogenase for up to 48 hr, followed by a decrease to normal level of cytochrome P-450 in 8 days. On the eighth day glucuronolactone dehydrogenase activity was still nearly two-fold in comparison with the controls. The results indicate that successive phenobarbitone treatments do not result in any permanent memory effects in the metabolism of glucuronolactone dehydrogenase and cytochrome P-450, although if repeated with 4-day intervals a diminished inductive response was observed on the third treatment.

Hepatic drug-metabolising enzyme activity and duration of hexobarbitone anaesthesia in barbitone-dependent and withdrawn rats

The activity of several hepatic drug-metabolising enzymes and the duration of hexobarbitone anaesthesia were determined in barbitone-dependent and withdrawn rats. Rats were made dependent on barbitone sodium by the administration of increasing amounts in the drinking water over a 32-day period. Abrupt withdrawal was accompanied by a characteristic withdrawal syndrome. The body weight, liver weight and body weight/liver weight ratio were found to be increased during barbitone treatment and to fall after withdrawal. The liver protein and glycogen content did not change during barbitone treatment. Withdrawal produced a transient reduction in hepatic glycogen content but did not affect protein levels. The capacity of hepatic microsomal preparations to metabolise hexobarbitone, aminopyrine and prontosil and to conjugate o-aminophenol was increased by barbitone treatment. Following withdrawal, the enzyme activity fell below that of control animals Four months after withdrawal the liver enzyme activity was still subnormal. The acute administration of phenobarbitone to 4-month withdrawn animals was found to restimulate hepatic microsomal drug-metabolising enzymes but the level attained was not as high as that found in phenobarbitone-treated control rats. The same degree of tolerance to injected hexobarbitone, as indicated by reduction in sleeping time, was found at all stages of barbitone treatment. A hypersensitivity to hexobarbitone was produced by withdrawal. It is concluded that both the tolerance in barbitone-dependent rats and the hypersensitivity of withdrawn animals can be adequately explained by altered hepatic drug-metabolising enzyme activity.

AN EFFECT OF PHENOBARBITONE ON GRISEOFULVIN METABOLISM IN THE RAT.

Prior administration of phenobarbitone to male and female rats dosed orally or intravenously with griseofulvin caused a fall in blood levels of the antibiotic. The effect of a single oral dose of phenobarbitone was significant after 12 hr and maximal between 12 and 48 hr, and it lasted for at least 96 hr; it was more pronounced when the barbiturate was administered repeatedly. Liver slices from animals dosed with phenobarbitone metabolized griseofulvin more rapidly than did those from undosed animals. The possible relevance of these findings to the clinical use of griseofulvin is discussed.

NEW METHOD OF PHENOBARBITONE ADMINISTRATION: IN THE TREATMENT OF EPILEPSY

NEW METHOD OF PHENOBARBITONE ADMINISTRATION: IN THE TREATMENT OF EPILEPSY

Exfoliative Dermatitis Following Phenobarbitone Administration

Exfoliative Dermatitis Following Phenobarbitone Administration